Abstract
Alternative splicing and expression of splice variants of genes in the brain may lead to the modulation of protein functions, which may ultimately influence behaviors associated with alcohol dependence and neurotoxicity. We recently showed that ethanol exposure can lead to pre-mRNA missplicing of Mcl-1, a pro-survival member of the Bcl-2 family, by downregulating the expression levels of serine/arginine rich splicing factor 1 (SRSF1). Little is known about the physiological expression of these isoforms in neuronal cells and their role in toxicity induced by alcohol exposure during the developmental period. In order to investigate the impact of alcohol exposure on alternative splicing of Mcl-1 pre-mRNA and its role in neurotoxicity, we developed a unique primary human neuronal culture model where neurospheres (hNSPs), neural progenitors (hNPCs), immature neurons, and mature neurons were cultured from the matching donor fetal brain tissues. Our data suggest that neural progenitors and immature neurons are highly sensitive to the toxic effects of ethanol, while mature neuron cultures showed resistance to ethanol exposure. Further analysis of Mcl-1 pre-mRNA alternative splicing by semi-quantitative and quantitative analysis revealed that ethanol exposure causes a significant decrease in Mcl-1L/Mcl-1S ratio in a dose and time dependent manner in neural progenitors. Interestingly, ectopic expression of Mcl-1L isoform in neural progenitors was able to recover the viability loss and apoptosis induced by alcohol exposure. Altogether, these observations suggest that alternative splicing of Mcl-1 may play a crucial role in neurotoxicity associated with alcohol exposure in the developing fetal brain.
Highlights
In the US about 10.2% women reports EtOH consumption with 3.1% reporting binge drinking during pregnancy[1,2,3]
We have recently shown that EtOH exposure of fetal neurons suppresses expression levels of serine/arginine rich splicing factor 1 (SRSF1) and causes missplicing of myeloid cell leukemia 1 (Mcl-1) by favoring the Mcl-1S
Our results suggest that human neurospheres, neural progenitors, and immature neurons but not the mature neurons are highly sensitive to the toxic effects of EtOH in a time and dose dependent manner
Summary
In the US about 10.2% women reports EtOH consumption with 3.1% reporting binge drinking during pregnancy[1,2,3]. Excessive neuronal death disrupts the development of normal neural networks and may lead to structural changes along with cognitive and behavioral dysfunctions[7,8]. The cellular mechanisms involved in increased neuronal death leading to altered structural changes and behavioral functions in. We have recently shown that EtOH exposure of fetal neurons suppresses expression levels of serine/arginine rich splicing factor 1 (SRSF1) and causes missplicing of myeloid cell leukemia 1 (Mcl-1) by favoring the Mcl-1S splicing over Mcl-1L24. In order to determine this, we investigated the potential impact of EtOH exposure on cellular toxicity and alternative splicing of Mcl-1 premRNA and its involvement with cytotoxicity induced by. EtOH in different lineages of neuronal cultures in an in vitro primary culture model where human neurospheres, neural progenitors, immature neurons, and mature neuron cultures were prepared and utilized from matching human fetal brain tissue. Overexpression of antiapoptotic Mcl-1L isoform in neural progenitor cells is able to reverse the viability loss and apoptosis induced by EtOH
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